This application renews a Research Scientist Award to enable Dr. Kosten to continue to pursue full time research and to train new researchers in the pharmacotherapy of cocaine and opioid dependence. During the last 5 years, Dr. Kosten has published over 100 articles, been a mentor for 5 junior faculty and 5 fellows, participated extensively in research reviews, and provided national and international consultations on pharmacotherapy. His broader roles include leadership in national organizations such as Presidency of the American Academy of Addiction Psychiatry and dissemination of buprenorphine treatment for opiate dependence through national education programs and leadership in the New England Clinical Trials Network. During the proposed award period, Dr. Kosten will continue mentoring and training activities and pursue two research goals. Goal 1 is to develop innovative cocaine pharmacotherapies (FDA Phase 1), conduct randomized clinical trials of them (FDA Phase 2), and develop new biomarkers of treatment response. Goal 2 is to use biological markers, such as genetic polymorphisms, to improve prediction of pharmacotherapy outcome and potentially match patients to the most effective treatment. His new NIDA Center (P50-DA18197) supports Goal 1 with a human laboratory for phase 1 testing of pharmacotherapies that currently include GABA agonists, and by 2006 will include a highly specific dopamine reuptake inhibitor (RTI 336) and a monoclonal antibody. Funded Phase 2 trials include: a cocaine vaccine, bupropion with contingency management, and 2 Center funded studies. A detailed Research Plan is provided for the cocaine vaccine study. This 20 week, randomized placebo-controlled, double blind clinical trial vaccinates 120 patients maintained on methadone for comorbid opioid and cocaine dependence. The Center's Phase 2 studies also address Goal 2 to examine pharmacogenetics of cocaine abuse treatment response. One study relates a functional polymorphism of dopamine beta hydroxylase to disulfiram response. Another study relates polymorphisms of GABA receptors and metabolism to treatment response with GABA agents, and a third relates the short/long promoter polymorphism of the serotonin transporter to treatment response with serotonin reuptake inhibitors. Coupled to these research goals are mentoring of junior researchers and the dissemination of information on new treatment approaches to addiction.